In science, profound changes in paradigm have emerged when previously unexplained phenomena, typically disregarded as noise or measurement error, are explained by a new theoretical structure. If a comparable phenomenon could be found in clinical medicine, an unexplained source of variance, it would be the so-called placebo effect. It should be noted that placebo effects have a different meaning for clinical trials and for neurobiologists. In the former case, they are considered non-specific, and contributing to the variability, noise, in treatment responses. This effect is particularly prominent in Major Depressive Disorder (MDD), a chronic and disabling illness that nevertheless presents with ? 30-50% responses attributable to placebo. For the neurobiologists, however, there is now uncontroversial evidence that the cognitive-emotional integrative processes that take place in the context of positive expectations associated with a potential therapeutic intervention, induce changes in brain function and neurochemistry that are associated with symptom improvement and illness recovery. In that context, true neurobiological placebo responses represent potential mechanisms of resiliency and treatment response, as well as new treatment target opportunities, as will be described in this application and backed by convincing preliminary data. This application proposes to examine non-specific and specific neurobiological contributions to treatment response, objectively explaining variance by studying the function of a neurotransmitter system linked with the regulation of stress, affect and mood, but also placebo responses, the endogenous opioid system and -opioid receptors. We are to determine interindividual variations in the function of -opioid receptor-mediated neurotransmission in patients diagnosed with moderate-severe MDD and the effect of placebo and active antidepressant administrations on these mechanisms. The data acquired will determine neurobiological factors that are associated with symptom improvement across non-specific and drug-specific conditions. Contributing variables that would explain variability in these mechanisms, specifically genetic variation, biomarkers and personality trait variation will be examined and pooled to develop markers of treatment response and orient novel approaches to the conduct of clinical trials. Some of these markers, specifically those linked to functional genetic polymorphisms would also direct the examination of novel treatment approaches not currently contemplated in drug target screening.